The therapeutic activities of some bile acids like, for instance, ursodeoxycholic, chenodeoxycholic, cholic and deoxycholic acids have been well known for some time. At first their use has been addressed to the dissolution of the cholesterol gall-stones, by virtue of their ability of inhibiting the cholesterol synthesis, helping the cholesterol removal through the formation of mixed micelles and inhibiting the cholesterol absorption in the intestine. Subsequently the bile acids have been used to treat biliary dyspepsias, biliary cirrhosis and chronic and cholestatic hepatopathies, as described in Digestive Diseases, 8, (1), 12-22, (1990) by Leuschner U. and Kurz W.
The oral therapy with bile acids until now has been carried out by means of the administration of the acids in form of immediate or delayed release tablets or capsules. All these formulations have the drawback of giving an incomplete absorption, due to scarce bioavailability as clearly shown by Parquet M. et al., European Journal of Clinical Investigation, 15, (4), 171-8, (1985), Igimi H., Corey M. C., J. Lip. Res., 21, 72-90, (1980) and Roda A., Fini A., Hepatology, 4, 72-6, (1984).
This scarce bioavailability is due to the fact that bile acids, particularly ursodeoxycholic acid, dissolve very slowly in the intestine after having crossed unabsorbed and undissolved the stomach.
The water solubility of free bile acids, mainly that of ursodeoxycholic acid, is very low (53 .mu.M) and, because of its restrained detergence (CMC=14 mM), its solubility is little increased with the increase of the pH and the complete solubilization takes place only at pH 8.47.
Therefore, ursodeoxycholic acid is completely solubilized and absorbed only when the intestinal pH exceeds the value of 8.4, while at lower values of pH a portion of ursodeoxycholic acid is not absorbed and undergoes a biotransformation to lithocholic acid by means of the intestinal bacterial flora.
Therefore it is easily understandable why delayed release formulations containing ursodeoxycholic acid actually can have a lesser bioavailability than that of immediate release formulations in case the delayed release takes place in the intestinal zones where a greater metabolization contemporaneously occurs together with a greater solubilization.
Overcoming the problems of scarce absorption of the immediate or delayed release formulations containing bile acids used at present, is the object of the present invention. This object is obtained by means of enterosoluble gastroresistant pharmaceutical formulations containing bile acids mixed with physiologically compatible basic substances which favour bile acids salification and therefore bile acids absorption in the intestinal tract.
The pharmaceutical formulations must be gastroresistant, because otherwise the strongly acid gastric juices would neutralize the basic substances so that they could not fulfill their function which consists of promoting bile acids solubilization by reacting with them in the intestine to originate the corresponding salts, which are soluble in the intestinal juice and therefore available for the absorption.
This object is achieved by the pharmaceutical formulations object of the present invention as it is clearly shown by biological tests of bioavailability carried out on men, by using a pharmaceutical formulation prepared according to the present invention in comparison with a commercial pharmaceutical formulation of ursodeoxycholic acid.
The experimental results showed a remarkable increase of the bioavailability of the formulation prepared according to the present invention in comparison with the commercial formulation. The average increase of the bioavailability (AUC) is equal to about 40%. Moreover the maximum hematic concentration (C max) reaches average values that are about three times higher and a quicker achievement of the maximum hematic peak (T max) is also noticed: in fact the formulation according to the present invention reached this peak in about 3 and half hours on the average while the commercial formulation reached it in about 4 hours and half.
These experimental data on men clearly show the full achievement of the object of the invention and therefore the pharmaceutical formulations object of the present invention are perfectly suitable for the therapeutic uses of the bile acids, mainly for the treatment of biliary calculoses. biliary dyspepsias, biliary cirrhosis and chronic and cholestatic hepatopathies.